Selective ep4 receptor antagonistic substance for treatment of cancer

ABSTRACT

This invention provides a medicament for the treatment of cancer, which cause a reduction of cancer. This invention relates to use of a compound which has inhibitory activities against prostaglandin E2 receptor (EP4 receptor) and is represented by the following general formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or the salt for the manufacture of a medicament for the treatment of cancer. The invention relates to a method for treatment of cancer comprising administering the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or the salt to humans or animals. The compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition may be used in combination with one or more second active agents.

This application is a continuation application of U.S. application Ser.No. 13/265,216, which issued as U.S. Pat. No. 8,921,391 on Dec. 30,2014, which is a U.S. national stage application of InternationalApplication No. PCT/JP2010/057114, filed Apr. 22, 2010.

TECHNICAL FIELD

This invention relates to use of a compound which has inhibitoryactivities against prostaglandin E2 receptor (EP4 receptor) and isrepresented by the following general formula (I), (II), (III), or (IV),or a pharmaceutically acceptable salt thereof (hereafter it is sometimescalled the compound of the present invention), or a pharmaceuticalcomposition comprising the compound or the salt for the manufacture of amedicament for the treatment of cancer. The invention relates to amethod for the treatment of cancer comprising administering the compoundof the present invention or a pharmaceutical composition comprising thesame to humans or animals. Further, this invention relates to apharmaceutical composition or a kit comprising the compound of thepresent invention or a pharmaceutically acceptable salt thereof.

BACKGROUND ART

Prostaglandins are mediators associated with various symptoms such aspain, fever and inflammation. Especially, prostaglandin E2 (PGE2) is apredominant eicosanoid detected in inflammation conditions. In addition,it is also involved in various physiological and/or pathologicalconditions such as hyperalgesia, uterine contraction, digestiveperistalsis, awakeness, suppression of gastric acid secretion, bloodpressure, platelet function, bone metabolism, angiogenesis, cancerinvasion and metastasis, and the like.

There are four receptor subtypes, EP1, EP2, EP3 and EP4, which displaydifferent pharmacological properties. EP4 receptor belongs to a Gprotein coupled receptor subfamily, is known as a receptor with seventransmembrane, and plays a significant role for biological events whichPGE2 relates to by stimulating cAMP production. From the aspect ofpharmacological studies, investigation of compounds with EP4 receptorantagonistic activities has been conducted and selective antagonistshave also been known.

PGE2 is a predominant eicosanoid detected in inflammation conditions,and in addition, it is also involved in various physiological and/orpathological conditions such as hyperalgesia, uterine contraction,digestive peristalsis, awakeness, suppression of gastric acid secretion,blood pressure, platelet function, bone metabolism, angiogenesis, cancermetastasis, and the like. Non-patent literature 1 to 3 disclose thecharacter of the prostanoid receptors, relationship thereof withtherapy, and selective agonists and antagonists most generally usedtherefor.

On the other hand, it is reported that PGE2 is highly expressed in thecancer tissue in the different types of cancer, and it is also clarifiedthat PGE2 relates to the development of cancer and disease condition. Itis known that PGE2 relates to activation of cell proliferation andinhibition of cell death (apoptosis) and plays an important role in theprocess of cancer progression and metastasis. But because of a lot ofreports varying depending on the difference of statuses such as cancertype, progress process and the like, at this time point, the medicalconsensus has never obtained on which PGE receptor mediates thesevarious functions of PGE2 associated with cancers.

Regarding the relation between EP4 and cancer, at the cellular level, areport (non-patent literature 4) which shows growth inhibition of thecolon cancer cell (HCA-7) by an EP4 receptor antagonist, L-161,982, hasbeen found. Regarding metastasis of cancer, a report (non-patentliterature 5) which shows metastasis suppression of breast cancer cellsby an EP4 receptor antagonist, AH23848 or ONO-AE3-208, and the like havebeen found.

Meanwhile, regarding the experiments using animals, it has been reportedthat an EP4 receptor antagonist, ONO-AE2-227 shows reduced formation ofazoxymethane-induced colon aberrant crypt foci and reduced formation ofintestinal polyp in APC gene knockout mice (non-patent literature 6).

As stated above, it is known that EP4 relates to development, growth andmetastasis of cancer, and in addition, reports which suggest prevention,growth inhibition, and metastasis suppression of cancer by EP4 receptorantagonists are also recognized. But the basis of cancer chemotherapy is“to shrink cancer tissues which have already been formed” and examplesof EP4 receptor antagonists which show shrinkage of cancer tissuesalready formed in animal organs have never been known, and there hasbeen a real need for such compounds.

CITATION LIST Non-Patent Literature

-   Non-patent Literature 1: Eicosanoids: From Biotechnology to    Therapeutic Applications, Folco, Samuelsson, Maclouf and Velo eds,    Plenum Press, New York, 1996, chapter 14, p. 137-154-   Non-patent Literature 2: Journal of Lipid Mediators and Cell    Signalling, 14: 83-87 (1996)-   Non-patent Literature 3: Prostaglandins and Other Lipid Mediators,    69: 557-573 (2002)-   Non-patent Literature 4: Experimental Cell Research Volume 313,    Issue 14, 15 Aug. 2007, Pages 2969-2979-   Non-patent Literature 5: Cancer Research, Volume 66, Issue 6, Mar.    15, 2006-   Non-patent Literature 6: Cancer Science Volume 94, Issue 7, 1 Jul.    2003, Pages 618-621; Cancer Research Volume 62, Issue 1, 1 Jan.    2002, Pages 28-32

SUMMARY OF INVENTION Technical Problem

The purpose of this invention is to provide a medicament for thetreatment of cancer in order to shrink cancer tissues.

Solution to Problem

After inventors of this invention conducted intensive research in orderto solve the said problem above, the inventors discovered that acompound of formula (I), (II), (III), or (IV) or a pharmaceuticallyacceptable salt thereof was dramatically able to shrink cancer tissueswhich were formed in animal cancer models and then completed the presentinvention.

Namely, the present invention is based on the finding that the compoundsof the present invention with EP4 selective antagonistic activity shranktumor mass when determining the effects of the EP4 selective antagonistson the mouse spontaneous gastric cancer model (K19-Wnt1/C2mE mice,Gastroenterology Volume 131, Pages 1086-1095, 2006). This gastric cancermodel involves PGE2-mediated mechanism of tumor progression, and theabove findings revealed first in the world that the compounds of theinvention have been proved effective in shrinking PGE2-mediated tumortissues. In addition, the compounds of the present invention also showedthe effects in the model of gastroenterological cancer, prostate cancer,lung cancer, and breast cancer.

Advantageous Effects of Invention

Therefore, the compound of this invention is useful for patients who arerequired to receive treatment for cancer which PGE2 relates to. “Cancerwhich PGE2 relates to” includes brain tumor, bone cancer, neoplasmderived from epithelial cells (epithelial cancer), for example, basalcell carcinoma, adenocarcinoma, gastroenterological cancer (e.g. lipcancer, oral cancer, esophageal cancer, intestinal cancer, colon cancerand gastric cancer), liver cancer, bladder cancer, pancreatic cancer,ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer(e.g. squamous cell and basal cell carcinoma), prostate cancer, renalcell carcinoma, and other known cancers which affect the epithelialcells in the body. Cancer is preferably selected fromgastroenterological cancer, prostate cancer, lung cancer, and breastcancer.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows change of mean tumor area of cross section in gastric tumormeasured by X-ray CT scan.

FIG. 2 shows comparison of relative gastric tumor volume between miceadministered a drug and age-matched mice administered no drug.

FIG. 3 shows change of mean tumor area of cross section in gastric tumormeasured by X-ray CT scan.

FIG. 4 shows comparison of relative colon tumor weight between miceadministered a drug and age-matched mice administered no drug.

FIG. 5 shows comparison of relative lung tumor weight between miceadministered a drug and age-matched mice administered no drug.

DESCRIPTION OF EMBODIMENTS

Compounds of the present invention which are useful for treatment ofcancer are compounds of formula (I), (II), (Ill), or (IV), orpharmaceutically acceptable salts thereof.

Compounds of the present invention include the solvates, complexes,polymorphs, prodrugs, isomers, and isotope-labeled compounds.

(wherein

Y¹, Y², Y³ and Y⁴ are independently selected from N, CH and C(L);

R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalky, C₁₋₈alkoxy, halo-substituted C₁₋₈ alkoxy, C₁₋₈ alkyl-S(O)_(m)—, Q¹-,pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- ordi-(C₁₋₈alkyl)amino, C₁₋₄alkylC(═O)—N(R³)— or C₁₋₄alkyl-S(O)_(m)—N(R³)—;wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl are optionallysubstituted with halo, C₁₋₃ alkyl, hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄alkyl-S(O)_(m)—, C₃₋₇ cycloalkyl-, cyano, indanyl,1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, pyrrolidinyl,piperidyl, oxopyrrolidinyl, oxopiperidyl, Q¹-, Q¹-C(═O)—, Q¹-O—,Q¹-S(O)_(m)—, Q¹-C₁₋₄alkyl-O—, Q¹-C₁₋₄alkyl-S(O)_(m)—,Q¹-C₁₋₄alkyl-C(O)—N(R³)—, Q¹-C₁₋₄alkyl-N(R³)— or C₁₋₄alkyl-C(O)—N(R³);

Q¹ is a 5- to 12-membered monocyclic or bicyclic aromatic ringoptionally containing up to 4 heteroatoms selected from O, N and S, andbeing optionally substituted with halo, C₁₋₄ alkyl halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, R³N(R⁴)C(═O)—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— or NH₂(HN═)C—;

A is a 5- to 6-membered monocyclic aromatic ring optionally containingup to 3 heteroatoms selected from O, N and S, wherein said 5- to6-membered monocyclic aromatic ring is optionally substituted with up to3 substituents selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, acetyl,R³N(R⁴)C(═O)—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino,C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— and NH₂(HN═)C—; B is halo-substitutedC₁₋₄ alkylene, C₃₋₇ cycloalkylene, C₂_₄ alkenylene, C₂₋₆ alkynylene,—O—C₁₋₅ alkylene, C₁₋₂ alkylene-O—C₁₋₂ alkylene or C₁₋₆ alkyleneoptionally substituted with an oxo group or C₁₋₃ alkyl;

W is NH, N—C₁₋₄ alkyl, O, S, N—OR⁵ or a covalent bond;

R² is H, C₁₋₄ alkyl, OH or C₁₋₄ alkoxy;

Z is a 5- to 12-membered monocyclic or bicyclic aromatic ring optionallycontaining up to 3 heteroatoms selected from O, N and S, wherein said 5-to 12-membered monocyclic or bicyclic aromatic ring is optionallysubstituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄alkenyl, C₁₋₄ alkynyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl,aminosulfonyl, C₁₋₄ alkylC(═O)—, R³C(═O)N(R⁴)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl, NH₂(HN═)C—,Q²-S(O)_(m)—, Q²-O—, Q²-N(R³)— or Q²-;

L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino,mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—,HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl,R³C(═O)N(R⁴)—, NH₂(HN═)C—, R³N(R⁴)C(═O), R³N(R⁴)S(O)_(m)—, Q²-,Q²-C(O)—, Q₂-O—, or Q²-C₁₋₄ alkyl-O—, or two adjacent L groups areoptionally joined together to form an alkylene chain having 3 or 4members in which one or two (nonadjacent) carbon atoms are optionallyreplaced by oxygen atom(s);

m is 0, 1 or 2;

R³ and R⁴ are independently selected from H and C₁₋₄ alkyl;

R⁵ is H, C₁₋₄ alkyl, C₁₋₄ alkyl-(O═)C— or C₁₋₄ alkyl-O—(O═)C—; and

Q² is a 5- to 12-membered monocyclic or bicyclic aromatic ring, or a 5-to 12-membered tricyclic ring optionally containing up to 3 heteroatomsselected from O, N and S, wherein said 5- to 12-membered monocyclic orbicyclic aromatic ring is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, hydroxyl, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino,mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄ alkyl-(O═)C—,R³(R⁴)C(═O)N—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino,C₃₋₇ cycloalkyl, C₁₋₄ alkyl-C(═O)NH— or NH₂(HN═)C—; or

when formula (I) includes OH and/or CO₂H, said OH and —COOH may beindependently esterified to form a pharmaceutically acceptable ester):

(wherein

ring A represents a phenyl group or a pyridyl group

ring B represents an aryl group or a heteroaryl group;

ring C represents a 1,4-phenylene group;

R¹ and R² independently represent a hydrogen atom, a halogen atom, analkyl group having from 1 to 4 carbon atoms, an alkoxy group having from1 to 4 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms,a haloalkoxy group having from 1 to 4 carbon atoms, a cyano group or anaminocarbonyl group;

R³ and R⁴ independently represent a hydrogen atom or an alkyl grouphaving from 1 to 4 carbon atoms; or R³ and R⁴ groups may be joinedtogether to form an alkylene chain having 2 to 6 carbon atoms:

R⁵ represents CO₂H, CO₂W.

R⁶ represents an alkyl group having 1 to 6 carbon atoms, a cycloalkylgroup having from 3 to 7 ring atoms, an aryl group or a heteroarylgroup;

X represents a methylene group, an oxygen atom or a sulfur atom;

said aryl group has from 6 to 10 carbon atoms;

said heteroaryl group is a 5- to 10-membered aromatic heterocyclic groupcontaining from 1 to 3 heteroatoms selected from the group consisting ofa sulfur atom, an oxygen atom and a nitrogen atom;

said aryl group and said heteroaryl group referred to in the definitionof ring B are unsubstituted or are substituted by at least onesubstituent selected from the group consisting of substituents alpha;

said 1,4-phenylene group referred to in the definition of ring C isunsubstituted or is substituted by at least one substituent selectedfrom the group consisting of substituents beta;

said aryl group and said heteroaryl group referred to in the definitionsof R⁶ and alpha are unsubstituted or are substituted by at least onesubstituent selected from the group consisting of substituents beta;

said substituents alpha are selected from the group consisting ofhalogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxygroups having from 1 to 4 carbon atoms, haloalkyl groups having from 1to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms,cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoylgroups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups havingfrom 7 to 10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups,alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups havingfrom 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups,hydroxyl groups, hydroxyalkyl groups having from 1 to 4 carbon atoms,nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms,alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylaminogroups having from 1 to 4 carbon atoms, alkanoyl(alkyl)amino groupshaving from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1to 6 carbon atoms each in both the alkanoyl and alkyl parts,alkanoyl(alkyl)amninoalkyl groups having from 1 to 6 carbon atoms eachin both the alkanoyl and each alkyl part, alkylsulfonylamino groupshaving from 1 to 4 carbon atoms, mono- or di-alkylaminocarbonyl groupshaving from 1 to 6 carbon atoms, mono- or di-alkylaminosulfinyl groupshaving from 1 to 6 carbon atoms, mono- or di-alkylaminosulfonyl groupshaving from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4carbon atoms, mono- or di-alkylamino groups having from 1 to 6 carbonatoms, mono- or di-alkylaminoalkyl groups having from 1 to 6 carbonatoms in each alkyl part, aralkyl groups having from 7 to 10 carbonatoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in thealkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms inthe alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbonatoms: or two adjacent alpha groups may be joined together to form analkylene or alkenylene chain having 3 or 4 carbon atoms:

said substituents beta are selected from the group consisting of halogenatoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groupshaving from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms andcyano groups; and

W is a pharmaceutically acceptable ester pro-drug group);

(wherein

X represents —CH— or a nitrogen atom;

Y represents —NR⁴, an oxygen atom or a sulfur atom;

R⁴ represents a hydrogen atom or an alkyl group having from 1 to 3carbon atoms;

Z represents a hydrogen atom or a halogen atom;

R¹ represents an alkyl group having from 1 to 6 carbon atoms optionallysubstituted with an alkoxy group having from 1 to 6 carbon atoms or acycloalkyl group having from 3 to 7 carbon atoms; a cycloalkyl grouphaving from 3 to 7 carbon atoms optionally substituted by an alkyl grouphaving from 1 to 3 carbon atoms; a phenyl group optionally substitutedwith one or more substituents alpha; or a group Het1 optionallysubstituted with one or more substituents alpha;

Het1 represents a heterocyclic group having from 4 to 7 ring atoms whichcontains either from 1 to 4 nitrogen ring heteroatoms, or from 0 to 2nitrogen ring heteroatoms and 1 oxygen or sulfur ring heteroatom;

R² and R³ independently represent a hydrogen atom or an alkyl grouphaving from 1 to 3 carbon atoms; or R² and R³ groups together form analkylene chain having from 3 to 6 carbon atoms; and

said substituent alpha is selected from the group consisting of halogenatoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groupshaving from 1 to 4 carbon atoms, hydroxy groups, alkoxy groups havingfrom 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbonatoms, cyano groups, hydroxyalkyl groups having from 1 to 4 carbonatoms, alkoxyalkyl groups having from 1 to 4 carbon atoms in each of thealkoxy and alkyl groups, alkylsulfonyl groups having from 1 to 4 carbonatoms, alkanoyl groups having from 2 to 5 carbon atoms, alkenyl groupshaving from 2 to 4 carbon atoms, alkynyl groups having from 2 to 4carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, nitrogroups, amino groups, mono- or di-alkylamino groups having from 1 to 4carbon atoms, aminosulfonyl groups, alkoxycarbonyl groups having from 1to 4 carbon atoms, alkylsulfonylamino groups having from 1 to 4 carbonatoms, cycloalkyl groups having from 3 to 7 carbon atoms and a mono- ordi-alkylaminocarbonyl groups having from 1 to 6 carbon atoms; or

when formula (III) includes a hydroxy group and/or a carboxy group, thehydroxy group and the carboxy group may be independently esterified toform a pharmaceutically acceptable ester); and

(wherein

X represents —CH or a nitrogen atom;

Y represents NR⁴, an oxygen atom or a sulfur atom;

R⁴ represents a hydrogen atom or an alkyl group having from 1 to 3carbon atoms;

Z represents a hydrogen atom or a halogen atom;

R¹ represents an alkyl group having from 1 to 6 carbon atoms optionallysubstituted with 1 to 2 groups independently selected from an alkoxygroup having from 1 to 6 carbon atoms, a trifluoromethyl group, analkanoyl group having from 2 to 5 carbon atoms, a cycloalkyl grouphaving from 3 to 7 carbon atoms, a phenyl group, a phenoxy group, aheterocyclic group and a heteroaryl group; a cycloalkyl group havingfrom 3 to 7 carbon atoms optionally substituted with an alkyl grouphaving from 1 to 3 carbon atoms; or a heterocyclic group:

R² and R³ independently represent a hydrogen atom or an alkyl grouphaving from 1 to 3 carbon atoms; or R² and R³ groups together form analkylene chain having from 3 to 6 carbon atoms;

said heteroaryl group is a 4 to 7-membered aromatic ring system havingeither from 1 to 4 nitrogen ring heteroatoms, or 0 to 2 nitrogen ringheteroatoms and 1 oxygen or sulfur ring heteroatom;

said heterocyclic group is a 4 to 7-membered saturated ring systemhaving either from 1 to 4 nitrogen ring heteroatoms, or 0 to 2 nitrogenring heteroatoms and 1 oxygen or sulfur ring heteroatom;

said phenyl group, phenoxy group and heteroaryl group referred to in thedefinition of R¹ are unsubstituted or are substituted by at least onesubstituent selected from the group consisting of substituents alpha;and

said substituent alpha is selected from the group consisting of halogenatoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groupshaving from 1 to 4 carbon atoms, hydroxyl groups, alkoxy groups havingfrom 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbonatoms, cyano groups, hydroxyalkyl groups having from 1 to 4 carbonatoms, alkoxyalkyl groups having from 1 to 4 carbon atoms in each of thealkoxy and alkyl groups, alkylsulfonyl groups having from 1 to 4 carbonatoms, alkanoyl groups having from 2 to 5 carbon atoms, alkenyl groupshaving from 2 to 4 carbon atoms, alkynyl groups having from 2 to 4carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, nitrogroups, amino groups, mono- or di-alkylamino groups having from 1 to 4carbon atoms, aminosulfonyl groups, alkoxycarbonyl groups having from 1to 4 carbon atoms, alkylsulfonylamino groups having from 1 to 4 carbonatoms, cycloalkyl groups having from 3 to 7 carbon atoms and a mono- ordi-alkylaminocarbonyl groups having from 1 to 6 carbon atoms; or

when formula (IV) includes OH and/or CO₂H, said OH and CO₂H may beindependently esterified to form a pharmaceutically acceptable ester).

Preferably, compounds of the present invention, which are useful for thetreatment of cancer, in formula (I) are:

-   3-[2-(4-{2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]urea;-   1-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)propan-2-yl    N-[(4-methylbenzene)sulfonyl]carbamate;-   3-{2-(4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)ethyl}-1-[(4-methylbenzene)sulfonyl]urea;-   1-{2-[4-(5-acetyl-2-ethyl-1H-1,3-benzothiazol-1-yl)phenyl]ethyl}-3-[(4-methylbenzene)sulfonyl]urea;-   3-{2-[4-(2-ethyl-5-methoxy-1H-1,3-benzothiazol-1-yl)phenyl]ethyl}-1-[(4-methylbenzene)sulfonyl]urea;-   2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   3-{2-[4-(6-chloro-5-cyano-2-ethyl-1H-1,3-benzothiazol-1-yl)phenyl]ethyl}-1-[(4-methylbenzene)sulfonyl]urea;-   2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   2-(4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   2-(4-{2-tertiary-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   2-(4-{2-amino-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   3-{2-[4-(6-chloro-2-ethyl-5-methanesulfonyl-1H-1,3-benzothiazol-1-yl)phenyl]ethyl}-1-[(4-methylbenzene)sulfonyl]urea;-   2-[4-(5-carbamoyl-6-chloro-2-ethyl-1H-1,3-benzothiazol-1-yl)phenyl]ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   1-(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl)-3-[(4-methylbenzene)sulfonyl]urea;-   1-(2-{4-[2-ethyl-5-(2-hydroxypropan-2-yl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl)-3-[(4-methylbenzene)sulfonyl]urea;-   1-(2-{4-[6-chloro-2-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl)-3-[(4-methylbenzene)sulfonyl]urea;-   N-[1-(6-chloro-1-{4-[2-({[(4-methylbenzene)sulfonyl]carbamoyl}amino)ethyl]phenyl}-5-(trifluoromethyl)-1H-1,3-benzothiazol-2-yl)ethyl]acetamide;-   6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylbenzene)sulfonyl]carbamoyl})amino]ethyl}phenyl)-1H-1,3-benzothiazol-5-carboxamide;-   2-{4-[6-chloro-2-(pyridin-2-yl)-5-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   3-(2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]pyridin-2-yl}ethyl)-1-[(4-methylbenzene)sulfonyl]urea;-   2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl    N-[(2-chlorobenzene)sulfonyl]carbamate; or-   3-(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)-1-[(4-methylbenzene)sulfonyl]urea;

in formula (II) are;

-   4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1({[5-chloro-2-(3-cyanophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3-chlorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(3-fluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(3-chlorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(2-chloro-4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(2,6-difluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3,4-difluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(2,3-difluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(2,5-difluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(2-chloro-5-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3-methylphenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3,5-difluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(2,3-difluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(3,4-difluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3-chloro-1-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(3,5-difluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(2,5-difluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3-chloro-5-methylphenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(3-methylphenoxy)benzoyl]amino}ethyl)benzoic    acid;-   ((1S)-1-{[5-chloro-2-(3-chloro-5-fluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(2,6-difluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-((1S)-1-{[(5-chloro-2-phenoxypyridin-3-yl)carbonyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(2,3-dichlorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3,4-dichlorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3,5-dichlorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid; or-   4-[(1S)-1-({[5-chloro-2-(3-fluoro-4-methylphenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;

in formula (III) are;

-   4-[(1S)-1-({5-chloro-2-[(4-chlorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(4-methylphenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3-chlorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(4-fluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2,3-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3,4-difluorophenoxy)methy    l]benzoyl}amino)ethyl]benzoic acid;-   4-[(1S)-1-({5-chloro-2-[(2,4-difluorophenoxy)methy    l]benzoyl}amino)ethyl]benzoic acid;-   4-{(1S)-1-[({5-chloro-2-[(3-chlorophenoxy)methyl]pyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2-chlorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3,5-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-{(1S)-1-[({5-chloro-2-[(4-chlorophenoxy)methyl]pyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3-fluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2,6-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2-fluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2,5-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-{(13)-1-[({2-[(4-chlorophenoxy)methyl]-5-fluoropyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid; or-   4-{(1S)-1-({5-chloro-2-[(cyclohexylmethoxy)methyl]benzoyl}amino)ethyl}benzoic    acid; and

in formula (IV) are;

-   4-[(1S)-1-({5-chloro-2-[(2-chlorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[2-(2-methylphenyl)ethoxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[2-(4-methylphenyl)ethoxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3-chlorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(4-chlorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(cyclobutylmethoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(cyclohexyloxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2-cyanobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[2-(4-fluorophenyl)ethoxy]benzoyl}amino)ethyl]benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(3-methylbutoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(4-fluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[2-(2-fluorophenyl)ethoxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2,5-difluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[({5-chloro-2-[2-(2-methylphenyl)ethoxy]benzoyl}amino)methyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2-chloro-4-fluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(2-phenoxyethoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3,4-difluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-{(1S)-1-[({5-chloro-2-[(4-chlorobenzyl)oxy]pyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-((1S)-1-{[2-(benzyloxy)-5-chlorobenzoyl]amino}ethyl)benzoic acid;-   4-{(1S)-1-[({5-chloro-2-[(2-chlorobenzyl)oxy]pyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-{(1S)-1-[({5-chloro-2-[2-(4-chlorophenyl)ethoxy]pyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3,5-difluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid; or-   4-[(1S)-1-({5-chloro-2-[2-(2,6-difluorophenyl)ethoxy]benzoyl}amino)ethyl]benzoic    acid; or    a pharmaceutically acceptable salt thereof.

More preferably, compounds of the present invention, which are usefulfor the treatment of cancer, in formula (I) are;

-   3-[2-(4-{2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]urea;-   3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]urea;-   1-{2-[4-(5-acetyl-2-ethyl-1H-1,3-benzothiazol-1-yl)phenyl]ethyl}-3-[(4-methylbenzene)sulfonyl]urea;-   3-{2-[4-(2-ethyl-5-methoxy-1H-1,3-benzothiazol-1-yl)phenyl]ethyl}-1-[(4-methylbenzene)sulfonyl]urea;-   2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   3-{2-[4-(6-chloro-5-cyano-2-ethyl-1H-1,3-benzothiazol-1-yl)phenyl]ethyl}-1-[(4-methylbenzene)sulfonyl]urea;-   2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   2-(4-(2-tert-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   2-[4-(5-carbamoyl-6-chloro-2-ethyl-1H-1,3-benzothiazol-1-yl)phenyl]ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   1-(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl)-3-[(4-methylbenzene)sulfonyl]urea;-   1-(2-{4-[6-chloro-2-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl)-3-[(4-methylbenzene)sulfonyl]urea;-   2-{4-[6-chloro-2-(pyridin-2-yl)-S-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl    N-[(4-methylbenzene)sulfonyl]carbamate;-   3-(2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]pyridin-2-yl}ethyl)-1-[(4-methylbenzene)sulfonyl]urea;-   2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-1,3-benzothiazol-1-yl]phenyl}ethyl    N-[(2-chlorobenzene)sulfonyl]carbamate; or-   3-(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)-1-[(4-methylbenzene)sulfonyl]urea;

in formula (II) are;

-   4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3-cyanophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3-chlorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(3-fluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(3-chlorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(2-chloro-4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({[5-chloro-2-(3,4-difluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid,-   4-[(1S)-1-({[5-chloro-2-(2,3-difluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid,-   4-((1S)-1-{[5-chloro-2-(2,3-difluorophenoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(3,4-difluorophenoxy)benzoyl]amino}ethyl)benzoic    acid; or-   4-[(1S)-1-({[5-chloro-2-(3-chloro-5-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid;

in formula (MI) are;

-   4-[(1S)-1-({5-chloro-2-[(4-chlorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3-chlorophenoxy)methyl]benzyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(4-fluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3,4-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2,4-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-{(1S)-1-[({5-chloro-2-[(3-chlorophenoxy)methyl]pyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3,5-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3-fluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic    acid;-   4-{(1S)-1-[({2-[(4-chlorophenoxy)methyl]-5-fluoropyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid; or-   4-{(1S)-1-({5-chloro-2-[(cyclohexylmethoxy)methyl]benzoyl}amino)ethyl}benzoic    acid; and

in formula (IV) are;

-   4-[(1S)-1-({5-chloro-2-[(2-chlorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3-chlorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-{[5-chloro-2-(4-chlorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(cyclobutylmethoxy)benzoyl]amino}ethyl)benzoic    acid;-   4-((1S)-1-{[5-chloro-2-(cyclohexyloxy)benzoyl]amino}ethyl)benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2-cyanobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[2-(4-fluorophenyl)ethoxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(4-fluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[2-(2-fluorophenyl)ethoxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(2-chloro-4-fluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid;-   4-{(1S)-1-[({5-chloro-2-[(4-chlorobenzyl)oxy]pyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-{(1S)-1-[({5-chloro-2-[(2-chlorobenzyl)oxy]pyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-{((1S)-1-[({5-chloro-2-[2-(4-chlorophenyl)ethoxy]pyridin-3-yl}carbonyl)amino]ethyl}benzoic    acid;-   4-[(1S)-1-({5-chloro-2-[(3,5-difluorobenzyl)oxy]benzoyl}amino)ethyl]benzoic    acid; or-   4-[(1S)-1-({5-chloro-2-[2-(2,6-difluorophenyl)ethoxy]benzoyl}amino)ethyl]benzoic    acid; or    a pharmaceutically acceptable salt thereof.

These compounds are disclosed in WO 02/32900, WO 2005/021508, WO05/105732, and WO 2005/105733.

Pharmaceutically acceptable salts include acid addition salts and basesalts thereof. Suitable acid addition salts are usually formed fromacids which form non-toxic salts. Examples include the acetate,aspartate, benzoate, besylate, bicarbonate/carbonate,bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate,formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are usually formed from bases which form non-toxicsalts. Examples include the aluminum, arginine, benzathine, calcium,choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine,olamine, potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

A pharmaceutically acceptable salt of a compound of formula (I), (II),(III), or (IV) may be readily prepared by mixing together solutions ofthe compound of formula (I), (II), (III), or (IV) and the desired acidor base, as appropriate. The salt may be precipitated from solution andbe collected by filtration, or may be recovered by evaporation of thesolvent. The degree of ionization in the salt may vary from completelyionized to almost non-ionized.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionized, partially ionized, or non-ionized. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter, all references to compounds of formula (I), (II), (III), or(IV) include references to salts, solvates and complexes thereof and tosolvates and complexes of salts thereof.

The compounds of the invention include compounds of the presentinvention as hereinbefore defined, polymorphs, prodrugs, and isomersthereof (including optical, geometric and tautomeric isomers) andisotopically-labeled compounds of the present invention as hereinafterdefined.

As stated above, the invention includes all polymorphs of the compoundsof the present invention as hereinbefore defined.

Also within the scope of the invention are so-called ‘prodrugs’ of thecompounds of formula (I), (II), (III), or (IV). Thus, certainderivatives of compounds of formula (I), (II), (III), or (IV) which mayhave little or no pharmacological activity themselves can, whenadministered into or onto the body, be converted into compounds offormula (I), (II), (HI), or (IV) having the desired activity, forexample, by hydrolytic cleavage. Such derivatives are referred to as‘prodrugs’. Further information on the use of prodrugs may be found in‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T.Higuchi and W. Stella) and ‘Bioreversible Carriers in Drug Design’,Pergamon Press, 1987 (ed. E. B. Roche, American PharmaceuticalAssociation).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I), (U), (III), or (IV) with certain moieties known to thoseskilled in the art as ‘pro-moieties’ as described, for example, in“Design of Prodrugs” by H Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include:

(i) where the compound of the present invention contains a carboxylicacid functionality (—COOH), an ester thereof obtainable by, for example,replacement of the hydrogen with (C₁-C₆)alkyl:

(ii) where the compound of the present invention contains an alcoholfunctionality (—OH), an ether thereof obtainable by, for example,replacement of the hydrogen with (C₁-C₆)alkanoyloxymethyl; and

(iii) where the compound of the present invention contains a primary orsecondary amino functionality (—NH₂ or —NHR where R≠H), an amide thereofobtainable by, for example, replacement of one or both hydrogens with(C₁-C₁₀)alkanoyl.

Further examples of substituent groups other than the foregoing examplesare known to skilled in the art and can be found in the aforementionedreferences, but not limited to them.

Finally, certain compounds of formula (I), (II), (III), or (IV) maythemselves also act as prodrugs of other compounds of the presentinvention.

Compounds of the present invention containing one or more asymmetriccarbon atoms can exist as two or more stereoisomers. Where a compound ofthe present invention contains an alkenyl or alkenylene group, geometriccis/trans (or Z/E) isomers are possible. Where the compound contains,for example, a keto or oxime group or an aromatic moiety, tautomericisomerism (‘tautomerism’) can occur. It follows that a single compoundmay exhibit more than one type of isomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof the present invention, including compounds exhibiting more than/equalto two type of isomerism, and mixtures of one or more thereof. Alsoincluded are acid addition salts or base salts wherein the counter ionis optically active, for example, D-lactate or L-lysine, or racemic, forexample, DL-tartrate or DL-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallization.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor and resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of the present invention contains an acidicor basic moiety, an acid or base such as tartaric acid or1-phenylethylamine. The resulting diastereomeric mixture may beseparated by chromatography and/or fractional crystallization and one orboth of the diastereoisomers can be converted to the corresponding pureenantiomer(s) by means well known to a skilled person.

Chiral compounds of the present invention (and chiral precursorsthereof) may be obtained in enantiomerically-enriched form usingchromatography, typically HPLC, on an asymmetric resin with a mobilephase consisting of a hydrocarbon, typically heptane or hexane,containing from 0 to 50 (w/w) % isopropanol, typically from 2 to 20(w/w) %, and from 0 to 5 (w/w) % of an alkylamine, typically 0.1 (w/w) %diethylamine. Concentration of the eluate affords the enriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art—see, for example, Stereochemistry ofOrganic Compounds by E L Eliel (Wiley, New York, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labeled compounds of the present invention wherein one ormore atoms are replaced by atoms having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberusually found in nature.

Examples of isotopes suitable for inclusion in the compounds of thepresent invention include isotopes of hydrogen, such as ²H and ³H,carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, suchas ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N,oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur,such as ³⁵S.

Certain isotopically-labeled compounds of the present invention, forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies associated with cancertherapy which includes diagnosis, alleviation of symptoms, improvementof QOL, and prophylaxis. The radioactive isotopes tritium, i.e. ³H, andcarbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view oftheir ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of the present invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the presentinvention include those wherein the solvent for crystallization may beisotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the present invention intended for pharmaceutical use maybe administered as crystalline or amorphous products. They may beobtained, for example, as solid plugs, powders, or films by methods suchas precipitation, crystallization, freeze drying, spray drying, andevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (second therapeutic agent (second active agent)) (or as anycombination thereof). Generally, they will be administered as aformulation in association with one or more pharmaceutically acceptableadditives. The term “additive” is used herein to describe any ingredientother than the compound(s) of the invention. The choice of additive willto a large extent depend on factors such as the particular mode ofadministration, the effect of the additive on solubility and stability,and the nature of the dosage form.

Thus, the present invention provides a combination of a compound of thisinvention, a solvate thereof, or a prodrug thereof with one or moreother pharmaceutically active agents (or compound group, the secondtherapeutic agent). In addition, the present invention provides apharmaceutical composition comprising such a combination in associationwith a pharmaceutically acceptable additive, diluent, or carrier,particularly for the treatment of cancer which EP4 antagonists relateto. Also, the present invention provides a kit comprising: a firstpharmaceutical composition comprising a compound of general formula (I),(II), (III), or (IV), or a pharmaceutically acceptable salt thereof: asecond active agent; and a container.

A kit for the treatment of cancer, which comprises the compound ofgeneral formula (I), (II), (III), or (IV), or the pharmaceuticallyacceptable salt thereof, is also one of the inventions. A commercialpackage comprising a pharmaceutical composition containing the compoundof general formula (I), (II), (III), or (IV), or the pharmaceuticallyacceptable salt thereof and a written matter associated with thepharmaceutical composition, wherein the written matter states that saidpharmaceutical composition can or should be used for treating cancer isalso one of the inventions.

Definition of Term

The skilled in the art can well understand the term in the presentspecification and claims attached, but the following terms have meaningsas described below.

The term “EP4 receptor activity” or “EP4 activity”, as used herein,means elevation of cAMP in association with PGE2 stimulation mediated byEP4 receptor.

The term “selective” EP4 receptor antagonist, as used herein, means aEP4 receptor antagonist with such an ability in inhibiting EP4 activitythat the IC₅₀, which is measured according to the standard method knownin the present field, shows at least 10 times, preferably 100 timeslower than IC₅₀ of EP1, EP2, or EP3 activity.

The terms “halo” and “halogen atom”, as used herein, refer to F, Cl, Bror I, preferably F or Cl.

The term “alkyl”, as used herein, means a straight or branched saturatedmonovalent hydrocarbon radical including, but not limited to, methyl,ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,neopentyl and the like.

The term “alkenyl”, as used herein, means a hydrocarbon radical havingat least one double bond including, but not limited to, ethenyl,propenyl, 1-butenyl, 2-butenyl and the like.

The term “alkynyl”, as used herein, means a hydrocarbon radical havingat least one triple bond including, but not limited to, ethynyl,propynyl, 1-butynyl, 2-butynyl and the like.

The term “cycloalkyl”, as used herein, means a saturated carbocyclicradical including, but not limited to, cyclopropyl, cyclobutyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and thelike.

The term “alkoxy”, as used herein, means an O-alkyl group wherein“alkyl” is as defined above, including, but not limited to methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, secondary-butoxy,tertiary-butoxy and the like.

In addition, for example, C₁₋₄ alkyl, as used herein, has the samemeaning as alkyl having one to four carbon atoms.

The term “alkylene”, as used herein, means saturated hydrocarbon(straight chain or branched) wherein a hydrogen atom is removed fromeach of the terminal carbons such as methylene, ethylene, propylene,butylene, pentylene, hexylene and the like.

The term “cycloalkylene”, as used herein, means a divalent cycloalkylgroup including, but not limited to, cyclopropylene, cyclobutylene,cyclopentylene, cyclohexylene, cycloheptylene and the like.

The term “alkenylene”, as used herein, means a straight or branchedhydrocarbon chain spacer radical having at least one double bondincluding, but not limited to, —CH═CH—, —CH═CHCH—, —CH═CHCH (CH₃)—, andthe like.

The term “alkynylene”, as used herein, means a straight or branchedhydrocarbon chain spacer radical having at least one triple bondincluding, but not limited to, —C≡C—, —C—C≡CCH₂—, —C≡CCH (CH₃)—, and thelike.

The term “alkanoyl”, as used herein, means a group having carbonyl suchas R′—C(O)— wherein R¹ is C₁₋₄ alkyl or C₃₋₄ cycloalkyl, including, butnot limited to formyl, acetyl, ethyl-C(O)—, n-propyl-C(O)—,isopropyl-C(O)—, n-butyl-C(O)—, iso-butyl-C(O)—, secondary-butyl-C(O)—,tertiary-butyl-C(O)—, cyclopropyl-C(O)—, cyclobutyl-C(O)— and the like.

The term “haloalkyl”, as used herein, means an alkyl radical which issubstituted by a halogen atom as defined above including, but notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl,trichloromethyl, iodomethyl and bromomethyl groups and the like.

The term “haloalkoxy”, as used herein, means haloalkyl-O—, including,but not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,2,2,2-trichloroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy,trichloromethoxy, iodomethoxy and bromomethoxy groups and the like.

The term “aryl”, as used herein, means an aromatic radical including,but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl,biphenyl and the like.

The term “monocyclic aromatic ring”, as used herein, means a monocyclicaromatic carbocyclic or heterocyclic ring (containing 0 to 4 heteroatomsselected from O, N and S) including, but not limited to, phenyl,pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl,thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl,pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl and thelike.

The term ‘bicyclic aromatic ring”, as used herein, means a monocyclic orbicyclic aromatic carbocyclic or heterocyclic ring (containing 0 to 4heteroatoms selected from O, N and S) including, but not limited to,naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl,isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinylquinoxalinyl and the like.

The term “tricyclic ring”, as used herein, means a saturated carbocyclicradical including, but not limited to, adamantyl,tricyclo[5.2.1.0^(2,6)]decyl, and the like.

The term “two adjacent L groups are optionally joined together to forman alkylene chain having 3 or 4 members in which one or two(non-adjacent) carbon atoms are optionally replaced by oxygen atom(s)”,as used herein, means, but not limited to, —O—CH₂—O—, —CH₂—O—CH₂—,—O—CH₂CH₂—, CH₂CH₂—O—, —O—CH₂CH₂—O—, —CH₂CH₂CH₂—O—, —O—CH₂CH₂CH₂—,—CH₂—O—CH₂CH₂—, —CH₂CH₂—O—CH₂—, and the like. The term “two adjacent Lgroups” means two L groups which bind to separate carbon atoms adjacentto each other. The said above “two non-adjacent carbon atoms” means thatthey may be two adjacent carbon atoms or may be two non-adjacent carbonatoms.

The term “ester” means a protecting group which can be cleaved in vivoby a biological method such as hydrolysis and forms a free acid or asalt thereof. Whether a compound is such a derivative or not can bedetermined by administering it by intravenous injection to anexperimental animal, such as a rat or mouse, and then studying the bodyfluids of the animal to determine whether or not the compound or apharmaceutically acceptable salt thereof can be detected.

Preferred examples of groups for an ester of a carboxyl group or ahydroxy group include: (1) aliphatic alkanoyl groups, for example:alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl,pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl,3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl,3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl,tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl,14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl,15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl,nonadecanoyl, icosanoyl and henicosanoyl groups; halogenatedalkylcarbonyl groups such as chloroacetyl, dichloroacetyl,trichloroacetyl, and trifluoroacetyl groups; alkoxyalkanoyl groups suchas a methoxyacetyl group; and unsaturated alkanoyl groups such asacryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl and(E)-2-methyl-2-butenoyl groups;

(2) aromatic alkanoyl groups, for example: arylcarbonyl groups such asbenzoyl, alpha-naphthoyl and beta-naphthoyl groups; halogenatedarylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyol groups;alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl and4-toluoyl groups; alkoxylated arylcarbonyl groups such as a 4-anisoylgroup; nitrated arylcarbonyl groups such as 4-nitrobenzoyl and2-nitrobenzoyl groups; alkoxycarbonylated arylcarbonyl groups such as a2-(methoxycarbonyl)benzoyl group; and arylated arylcarbonyl groups suchas a 4-phenylbenzoyl group;

(3) alkoxycarbonyl groups, for example: alkoxycarbonyl groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,sec-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl groups; andhalogen- or tri(alkyl)silyl-substituted alkoxycarbonyl groups such as2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups;

(4) tetrahydropyranyl or tetrahydrothiopyranyl groups such astetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl,4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, and4-methoxytetrahydrothiopyran-4-yl groups; tetrahydrofuranyl ortetrahydrothiofuranyl groups such as tetrahydrofuran-2-yl andtetrahydrothiofuran-2-yl groups;

(5) silyl groups, for example: tri(alkyl)silyl groups such astrimethylsilyl, triethylsilyl, isopropyldimethylsilyl,t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl andtriisopropylsilyl groups; and silyl groups substituted by one or morearyl and alkyl groups such as diphenylmethylsilyl, diphenylbutylsilyl,diphenylisopropylsilyl and phenyldiisopropylsilyl groups;

(6) alkoxymethyl groups, for example: alkoxymethyl groups such asmethoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl,propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl groups;alkoxylated alkoxymethyl groups such as a 2-methoxyethoxymethyl group;and halo(alkoxy)methyl groups such as 2,2,2-trichloroethoxymethyl andbis(2-chloroethoxy)methyl groups;

(7) substituted ethyl groups, for example: alkoxylated ethyl groups suchas 1-ethoxyethyl and 1-(isopropoxy)ethyl groups; and halogenated ethylgroups such as a 2,2,2-trichloroethyl group; and

(8) aralkyl groups, for example: alkyl groups substituted by from 1 to 3aryl groups such as benzyl, alpha-naphthylmethyl, beta-naphthylmethyl,diphenylmethyl, triphenylmethyl, alpha-naphthyldiphenylmethyl and9-anthrylmethyl groups; alkyl groups substituted by from 1 to 3substituted aryl groups, where one or more of the aryl groups aresubstituted by one or more alkyl, alkoxy, nitro, halogen or cyanosubstituents such as 4-methylbenzyl, 2,4,6-trimethylbenzyl,3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl,2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and4-cyanobenzyl groups; alkenyloxycarbonyl groups such asvinyloxycarbonyl; aryloxycarbonyl groups such as phenoxycarbonyl; andaralkyloxycarbonyl groups in which the aryl ring may be substituted by 1or 2 alkoxy or nitro groups, such as benzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups.

The term “protecting group”, as used herein, means a hydroxy or aminoprotecting group which is selected from typical hydroxy or aminoprotecting groups described in Protective Groups in Organic Synthesisedited by T. W. Greene et al. (John Wiley & Sons, 1991).

The term ‘hydrate’ is employed when said solvent is water.

The term “treating” or “treatment”, as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treating” or “treatment”, as usedherein, includes not only shrinkage of grown tumor tissue but alsoalleviation of symptoms, improvement of QOL, and prophylaxis(radiotherapy, postoperative prevention of recurrence, adjuvantchemotherapy and the like).

Other features and advantages of the invention may be apparent from thefollowing detailed description and the claims. Although particularembodiments of the present invention have been described, various otherknown or usual changes and modifications in this field fall into thepresent invention and are within the claims. The present invention alsoincludes the equivalents, changes, uses, or variations, which are fromthe spirit of the present invention.

A compound of the present invention is administered in an enough amountfor reducing cancer metastasis, shrinking cancer, and/or enhancingeffectiveness of cancer therapy. Such a therapeutic effective amountvaries in accordance with the specific condition to be treated, thepatient's condition, the route of administration, the formulation, thefield decision, and other factors. In the light of the disclosure,depending on the things known to those skilled in the art, the amount isdecided by routine optimization techniques.

A pharmaceutical composition can comprise a compound of general formula(I), (II), (III), or (IV), or a pharmaceutically acceptable saltthereof. Such medicaments are mixed with a pharmaceutically acceptabletransport medium or carrier.

As used herein, the language “pharmaceutically acceptable transportmedium” includes solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration. The above mediummay also contain other active or inactive ingredients and is targeted tocancer tissues based on the composition.

Therapeutic efficacy of compounds of the present invention can bedetermined in light of this disclosure by standard therapeuticprocedures in cell cultures or experimental animals, e.g., fordetermining the ED₅₀ (the dose therapeutically effective in 50% of thepopulation).

The data obtained from cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage mayvary depending upon the formulation and the route of administration. Forany EP4 receptor antagonist used in the method of the invention, thetherapeutically effective dose can be estimated initially from cellculture assays. A dose may be formulated in animal models to achieve adesired circulating plasma concentration range based on the IC₅₀ asdetermined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography or massspectrometer.

It is well known to those skilled in the art that certain factors mayinfluence the dosage and timing required to effectively treat a mammal,the factors including, but not limited to, the severity of the diseaseor disorder, previous treatments, the general health and/or age of themammal, and other diseases present. Further, treatment of a mammal witha therapeutically effective amount of the compound of the presentinvention may include, but not limited to, a single treatment,alternate-day treatment, and a series of treatments.

The precise amount of the compounds administered to a human patient,will be particularly within the responsibility of the attendantphysician. However, the dose employed will depend upon a number offactors including the age and sex of the patient, the precise conditionbeing treated and its severity, and the route of administration.

The compounds are conveniently administered in the form ofpharmaceutical compositions. Such compositions may conveniently bepresented for use in conventional manner in admixture with one or morepharmaceutically acceptable carriers or excipients. Preferably, thepharmaceutical compositions are used for treatment of cancer. Thepharmaceutical compositions for the treatment of cancer comprising thecompounds of the present invention are also one of the presentinventions.

While it is possible for the compounds to be administered as a rawchemical, it is preferable to present it as a pharmaceuticalformulation. The formulations comprise the compounds together with oneor more acceptable carriers or diluents therefor and optionally othertherapeutic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof. A pharmaceuticalcomposition is formulated to meet the desirable route of administration.The administration route is, for example, parenteral (e.g. intravenous,intracutaneous, subcutaneous), oral (e.g. ingestion or inhalation),percutaneous (local), mucosal, rectal, and local (includingpercutaneous, buccal, and sublingual) administration. The solution orsuspension can be prepared by the method described in Remington'sPharmaceutical Sciences, (18^(th) ed., Gennaro, ed., Mack PublishingCo., Easton, Pa., (1990)).

The most suitable route may be different depending upon, for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All the methodsinclude the step of bringing into association the compound (“activeingredient”) with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andhomogeneously bringing into association the active ingredient withliquid carriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tablets(e.g. chewable tablets in particular for paediatric administration) eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as a solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active agent ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored so as toprovide slow or controlled release of the active ingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilized) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the kind previously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter, hard fat or polyethyleneglycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored base such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a base such as gelatinand glycerin or sucrose and acacia.

The compounds of the present invention or a pharmaceutically acceptablesalt thereof may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds of the present invention may be formulatedwith suitable polymeric or hydrophobic materials (for example as anemulsion in an acceptable oil) or ion exchange resins, or as sparinglysoluble derivatives, for example, as a sparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may contain other agents conventional in the art in thelight of the type of formulation in question, for example those suitablefor oral administration such as flavoring agents.

It is also beneficial to use the compound of the present invention orthe pharmaceutically acceptable salt thereof in combination with atleast one member selected from the steroidal or non-steroidalantiandrogen agent or antiestrogen agent, chemotherapeutic agent, GnRHantagonistic peptide, alpha-reductase inhibitor, alpha-receptorinhibitor, aromatase inhibitor, 17beta-hydroxysteroid dehydrogenaseinhibitor, adrenal androgen production inhibitor, kinase inhibitor, drugfor hormone therapy, and drug inhibiting cell growth factor or itsreceptor, among others.

The “chemotherapeutic agent” mentioned above includes ifosfamide,adriamycin, peplomycin, cisplatin, cyclophosphamide, 5-FU, UFT,methotrexate, mitomycin C, mitoxantrone, etc.

The “GnRH antagonistic peptide” mentioned above includes non-oral GnRHantagonistic peptides such as cetrorelix, ganirelix, abarelix, etc.

The “adrenal androgen production inhibitor” mentioned above includeslyase (C17, 20-lyase) inhibitors, etc.

The “kinase inhibitor” mentioned above includes tyrosine kinaseinhibitor, etc.

The “drug for hormone therapy” includes antiestrogens, progesterones(e.g., MPA, etc.), androgens, estrogens and antiandrogens, among others.

The “cell growth factor” may be any substance that promotesproliferation of cells and generally includes peptides with molecularweights not over 20.000 which express the action at low concentrationsthrough binding to receptors. Specifically, there can be mentioned (1)EGF (epidermal growth factor) or substances having substantially thesame activity (e.g., EGF, heregulin (HER2 ligand), etc.), (2) insulin orsubstances having substantially the same activity (e.g., insulin, IGF(insulin-like growth factor)-1, IGF-2, etc.), (3) FGF (fibroblast growthfactor) or substances having substantially the same activity (aFGF,bFGF, KGF (keratinocyte growth factor), HGF (hepatocyte growth factor),FGF-10, etc.), and (4) other growth factors (e.g., CSF (colonystimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF(nerve growth factor), PDGF (platelet-derived growth factor) and TGFbeta (transforming growth factor beta), etc.), among others.

The “cell growth factor receptor” may be any receptor capable of bindingto said cell growth factor, including EGF receptor, heregulin receptor(HER2), insulin receptor-1, insulin receptor-2, IGF receptor, FGFreceptor-1, FGF receptor-2, etc.

The drug inhibiting cell growth factor mentioned above includesherceptin (anti-HER2 receptor antibody), among others.

The drug inhibiting cell growth factor or its receptor mentioned aboveincludes herbimycin, PD 153035 [e.g., Science, 265 (5175) p 1093,(1994)], etc.

A further class of drugs inhibiting cell growth factor or its receptorincludes HER2 inhibitors. The HER2 inhibitor may be any substance thatinhibits the activity of HER2 (e.g., kinase activity), thus including anantibody, a low-molecular weight compound (synthetic or naturalproduct), an antisense, an HER2 ligand, heregulin, and any of them aspartially modified or mutated in structure. Moreover, it may be asubstance which inhibits HER2 activity by inhibiting HER2 receptor (e.g.anti-HER2 receptor antibody).

For prostatic cancer, there is used the compound of the presentinvention in combination with the GnRH super-agonist, antiandrogen,antiestrogen, chemotherapeutic agent (e.g., ifosfamide, UFT, adriamycin,peplomycin, cisplatin, etc.), GnRH antagonistic peptide, aromataseinhibitor, 17beta-hydroxysteroid dehydrogenase inhibitor, adrenalandrogen production inhibitor, kinase inhibitor, drug for hormonetherapy such as estrogens (e.g., DSB, EMIP, etc.), antiandrogens (e.g.,CMA, etc.), etc., drug inhibiting cell growth factor or its receptor, orthe like.

For breast cancer, there is used the compound of the present inventionin combination with the GnRH super-agonist, antiestrogen,chemotherapeutic agent (e.g., cyclophosphamide, 5-FU, UFT, methotrexate,adriamycin, mitomycin C, mitoxantrone, etc.). GnRH antagonistic peptide,aromatase inhibitor, adrenal androgen production inhibitor, kinaseinhibitor, drug for hormone therapy such as antiestrogens (e.g.,tamoxifen, etc.), progesterones (e.g., MPA, etc.), androgens, estrogens,etc., drug inhibiting cell growth factor or its receptor, or the like.

For gastroenterological cancer, there is used the compound of thepresent invention in combination with chemotherapeutic agent (e.g.,cyclophosphamide, 5-FU, UFT, methotrexate, levofolinate, gemsitabine,adriamycin, mitomycin C, mitoxantrone, etc.), microtubule inhibitor(e.g., vincristine, paclitaxel, etc.), platinum-containing drug e.g.,cisplatin, etc., topoisomerase inhibitor (e.g., irinotecan, etoposide,etc.), COX-2 inhibitor, kinase inhibitor, drug inhibiting cell growthfactor or its receptor, or the like.

For pulmonary cancer, there is used the compound of the presentinvention in combination with chemotherapeutic agent (e.g.,cyclophosphamide, 5-FU, UFT, methotrexate, adriamycin, mitomycin C,mitoxantrone, etc.), microtubule inhibitor (e.g., vincristine,paclitaxel, etc.), platinum-containing drug e.g., cisplatin, etc.,topoisomerase inhibitor (e.g., irinotecan, etoposide, etc.), kinaseinhibitor, drug inhibiting cell growth factor or its receptor, or thelike.

Second active agents that are small molecules can also be used toalleviate adverse effects associated with the administration of thecompounds of the present invention. However, like some large molecules,many are believed to be capable of providing a synergistic effect whenadministered with (e.g., before, after or simultaneously) the compoundsof the present invention. Examples of small molecule second activeagents include, but are not limited to, anti-cancer agents, antibiotics,immunosuppressive agents, and steroids.

Examples of anti-cancer agents include, but are not limited to,alkylating agents, anti-neoplastic agents, anti-metabolites (e.g.,folate analogs, purine analogs, adenosine analogs, pyrimidine analogs,and substituted ureas), platinum coordination complexes, topoisomeraseII inhibitors, and radiation.

Specific anticancer agents include, but are not limited to: acivicin;aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole;anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin;batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafidedimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;busulfan; cactinomycin; calusterone; capecitabine; caracemide;carbetimer, carboplatin; carmustine; carubicin hydrochloride;carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil;cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;erlotinib; esorubicin hydrochloride; estramustine; estramustinephosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine;fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;fludarabine phosphate; fluorouracil; flurocitabine; fosquidone;fostriecin sodium; gefitinib; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;paclitaxel; pegaspargase; peliomycin; pemetrexed; pentamustine;peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantronehydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin;prednimustine; procarbazine hydrochloride; puromycin; puromycinhydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanidine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other anti-cancer drugs include, but are not limited to; 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; autiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinyispermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspennine; dihydro-5-azacytidine;9-dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol;dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol;duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;eflornithine; elemene; emitefur; epirubicin; epristeride; estramustineanalogue; estrogen agonists; estrogen antagonists; etanidazole;etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide;filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane;fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathioneinhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;ilomastat; imatinib (e.g., Gleevec); imiquimod; immunostimulantpeptides; insulin-like growth factor-1 receptor inhibitor; interferonagonists; interferons; interleukins; iobenguane; iododoxorubicin;4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B;itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate;lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin;letrozole; leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidanne; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryllipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®);O⁶-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine;romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin;SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallinmstine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,rituximab, oblimersen (Genasense®), remicade, docetaxel, celecoxib,melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatin,temozolomide, etoposide, cyclophosphamide, temodar, carboplatin,procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa, taxol,taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11,interferon alpha, pegylated interferon alpha (e.g., PEGINTRON-A),capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomaldaunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2,GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busuiphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

In certain embodiments, the second active agent is etoposide,daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin,pemetrexed, methotrexate, Ara-C, 5-FU, wortmannin, gemcitabin,geldanamycin or a combination of one or more kinds thereof.

In other embodiments, the second active agent is a supportive careagent. An example of supportive care agent is an antiemetic. Specificantiemetic agents include, but are not limited to, phenothiazines,butyrophenones, benzodiazapines, corticosteroids, serotonin antagonists,cannabinoids, and NK₁ receptor antagonists. Examples of phenothiazineantiemetics include, but are not limited to, prochlorperazine andtrimethobenzamide. Examples of butyophenone antiemetic include, but arenot limited to, haloperidol. Examples of benzodiazapine antiemeticinclude, but are not limited to, lorazepam. Examples of corticosteroidantiemetic include, but are not limited to, dexamethasone. Examples ofserotonin antagonist antiemetic include, but are not limited to,ondansetron, granisetron, and dolasetron. Examples of cannabinoidantiemetic include, but are not limited to, dronabinol. Examples of NK₁receptor antagonists include, but are not limited to, aprepitant. Dosesand dosing regimens of antiemetic agents should depend on the specificindication being treated, age and condition of a patient, and severityof adverse effects, and may be adjusted accordingly by those of skill inthe art. Examples of doses and dosing regimens can be found, forexample, in The Physician's Desk Reference.

The invention also includes combining separate pharmaceuticalcompositions in a kit form. The kit comprises two or more separatepharmaceutical compositions: a compound of the present invention; and asecond active agent as described herein. The kit usually comprises acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral and parenteral), orare administered at different dosage intervals, or when titration of theindividual components of the combination is desired by the prescribingphysician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably, the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

Exemplary Methods of Combination Therapy

In certain embodiments, the methods provided herein compriseadministering the compounds of the present invention in combination withone or more second active agents, and/or in combination with radiationtherapy or surgery. The administration of the compounds of the presentinvention and the second active agents to a patient can occursimultaneously or sequentially by the same or different routes ofadministration. The suitability of a particular route of administrationemployed for a particular active agent will depend on the active agentitself (e.g., whether it can be administered orally without decomposingprior to entering the blood stream) and the disease being treated.Recommended routes of administration for the second active agents areknown to those of ordinary skill in the art. See, e.g., Physicians' DeskReference.

In one embodiment, the second active agent is administered intravenouslyor subcutaneously once or twice daily in an amount of from about 1 toabout 1,000 mg, from about 5 to about 500 mg, from about 10 to about 375mg or from about 50 to about 200 mg. In one embodiment, the secondactive agent is rituximab, oblimersen (Genasense®), GM-CSF, G-CSF, EPO,taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan,pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin,COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine or acombination thereof. In certain embodiments, the second active agent isetoposide, daunomycin, actinomycin D, mitomycin C, cisplatin,carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmamin,geldanamycin, gemcitabin or a combination thereof.

In another embodiment, provided herein are methods of treating,preventing and/or managing hematologic malignancies, which compriseadministering the compounds of the present invention in combination with(e.g., before, during or after) conventional therapy including, but notlimited to, surgery, immunotherapy, biological therapy, radiationtherapy and other non-drug based therapy presently used to treat,prevent or manage cancer. Without being limited by theory, it isbelieved that the compounds of the present invention may provideadditive or synergistic effects when given concurrently with suchconventional therapy.

In certain embodiments, the second active agent is co-administered withthe compounds of the present invention or administered with approximate1 to 50 hour delay. In certain embodiments, the compounds of the presentinvention are administered first followed by administration of thesecond active agent with approximate 1 to 50 hour delay. In otherembodiments, the second active agent is administered first followed byadministration of the compounds of the present invention withapproximate 1 to 50 hour delay. In some embodiments, the delay ispreferably 24 hours.

In one embodiment, the compounds of the present invention can beadministered in a daily amount of from about 1 to about 5000 mg alone orin combination with a second active agent disclosed herein, prior to,during, or after the use of conventional therapy.

In another embodiment, the methods provided herein comprise: a)administering to a patient in need thereof, a daily dose of about 1 mgto 5000 mg of the compounds of the present invention and b)administering a therapeutically effective amount of a second activeagent such as a supportive care agent.

In one embodiment, the second agent is an alkylating agent. In anotherembodiment, the alkylating agent is an alkyl sulfonate and the cancerbeing treated is usually leukemia or lymphoma. In another embodiment,the alkyl sulfonate is busulfan. In another embodiment, the alkylsulfonate is busulfan and the therapeutically effective amount isusually a daily dose of at least 1 mg. In another embodiment, the alkylsulfonate is busulfan and the therapeutically effective amount isusually a daily oral dose of between about 2 mg and 8 mg. In anotherembodiment, the alkyl sulfonate is busulfan and the therapeuticallyeffective amount is usually a daily oral dose of between about 1 mg andabout 3 mg.

In another embodiment, the alkylating agent is a nitrogen mustard andthe cancer being treated is usually bladder cancer, breast cancer,Hodgkin's disease, leukemia, lung cancer, melanoma, ovarian cancer, ortesticular cancer. In another embodiment, the nitrogen mustard ischlorambucil. In another embodiment, the nitrogen mustard ischlorambucil and the therapeutically effective amount is usually atleast 0.1 mg/kg. In another embodiment, the nitrogen mustard ischlorambucil and the therapeutically effective amount is usually a dailyoral dose of between about 0.1 mg/kg and about 0.2 mg/kg for three tosix weeks. In another embodiment, the nitrogen mustard is chlorambuciland the therapeutically effective amount is usually a dose of 0.4 mg/kgevery three to four weeks. In another embodiment, the nitrogen mustardis cyclophosphamide. In another embodiment, the nitrogen mustard iscyclophosphamide and the therapeutically effective amount is usually anintravenous dose of at least 10 mg/kg. In another embodiment, thenitrogen mustard is cyclophosphamide and the therapeutically effectiveamount is usually an intravenous dose between about 10 mg/kg and about15 mg/kg every seven to ten days. In another embodiment, the nitrogenmustard is cyclophosphamide and the therapeutically effective amount isusually an oral daily dose between about 1 mg/kg and about 5 mg/kg. Inanother embodiment, the nitrogen mustard is melphalan. In anotherembodiment, the nitrogen mustard is melphalan and the therapeuticallyeffective amount is usually a daily oral dose of at least 2 mg. Inanother embodiment, the nitrogen mustard is melphalan and thetherapeutically effective amount is usually a daily oral dose of 6 mgfor two to three weeks, no melphalan for two to four weeks and then adaily oral dose of between about 2 mg and about 4 mg. In anotherembodiment, the nitrogen mustard is melphalan and the therapeuticallyeffective amount is usually a daily oral dose of 10 mg/m² (body surfacearea) for four days every four to six weeks.

In another embodiment, the alkylating agent is a nitrosourea and thecancer being treated is usually brain tumor, colorectal cancer,Hodgkin's disease, liver cancer, lung cancer, lymphoma, or melanoma. Inanother embodiment, the nitrosourea is carmustine. In anotherembodiment, the nitrosourea is carmustine and the therapeuticallyeffective amount is usually at least 150 mg/m². In another embodiment,the nitrosourea is carmustine and the therapeutically effective amountis usually an intravenous dose between about 150 mg/m² and 200 mg/m²every six to eight weeks.

In another embodiment, the alkylating agent is a triazene and the cancerbeing treated is usually Hodgkin's disease, melanoma, neuroblastoma, orsoft tissue sarcoma. In another embodiment, the triazene is dacarbazine.In another embodiment, the triazene is dacarbazine and thetherapeutically effective amount is usually a daily intravenous dose ofbetween about 2.0 mg/kg and about 4.5 mg/kg for ten days every fourweeks. In another embodiment, the triazene is dacarbazine and thetherapeutically effective amount is usually a daily intravenous dose of250 mg/m² for five days every three weeks. In another embodiment, thetriazene is dacarbazine and the therapeutically effective amount isusually an intravenous dose of 375 mg/m² every sixteen days. In anotherembodiment, the triazene is dacarbazine and the therapeuticallyeffective amount is usually an intravenous dose of 150 mg/m² for fivedays every four weeks.

In another embodiment, the second agent is an anti-neoplastic antibioticand the cancer being treated is usually bladder cancer, breast cancer,cervical cancer, head and neck cancer, Hodgkin's disease, leukemia,multiple myeloma, neuroblastoma, ovarian cancer, sarcoma, skin cancer,testicular cancer, or thyroid cancer. In another embodiment, theantibiotic is bleomycin. In another embodiment, the antibiotic isbleomycin and the therapeutically effective amount is usually at least10 units/m². In another embodiment, the antibiotic is bleomycin and thetherapeutically effective amount is usually an intravenous,subcutaneous, or intramuscular dose of between about 10 units/m² andabout 20 units/m² weekly or twice weekly. In another embodiment, theantibiotic is dactinomycin. In another embodiment, the antibiotic isdactinomycin and the therapeutically effective amount is usually atleast 0.01 mg/kg. In another embodiment, the antibiotic is dactinomycinand the therapeutically effective amount is usually a daily intravenousdose of between about 0.010 mg/kg and about 0.015 mg/kg for five daysevery three weeks. In another embodiment, the antibiotic is dactinomycinand the therapeutically effective amount is usually an intravenous doseof 2 mg/m² every three or four weeks. In another embodiment, theantibiotic is daunorubicin. In another embodiment, the antibiotic isdaunorubicin and the therapeutically effective amount is usually atleast 30 mg/m². In another embodiment, the antibiotic is daunorubicinand the therapeutically effective amount is usually a daily intravenousdose of between about 30 mg/m² and about 45 mg/m² for three days. Inanother embodiment, the antibiotic is a liposomal preparation ofdaunorubicin and the therapeutically effective amount is usually anintravenous dose of 40 mg/m² every two weeks. In another embodiment, theantibiotic is doxorubicin. In another embodiment, the antibiotic isdoxorubicin and the therapeutically effective amount is usually at least15 mg/m². In another embodiment, the antibiotic is doxorubicin and thetherapeutically effective amount is usually an intravenous dose ofbetween about 60 mg/m² and about 90 mg/m² every three weeks. In anotherembodiment, the antibiotic is doxorubicin and the therapeuticallyeffective amount is usually a weekly intravenous dose of between about15 mg/m² and about 20 mg/m². In another embodiment, the antibiotic isdoxorubicin and the therapeutically effective amount is usually a cyclecomprising a weekly intravenous dose of 30 mg/m² for two weeks followedby two weeks of no doxorubicin.

In another embodiment, the second agent is an anti-metabolite. Inanother embodiment, the anti-metabolite is a folate analog and thecancer being treated is usually breast cancer, head and neck cancer,leukemia, lung cancer, non-Hodgkin's lymphoma, or osteosarcoma. Inanother embodiment, the folate analog is methotrexate. In anotherembodiment, the folate analog is methotrexate and the therapeuticallyeffective amount is usually at least 2.5 mg. In another embodiment, thefolate analog is methotrexate and the therapeutically effective amountis usually a daily oral dose of between about 2.5 mg and about 5 mg. Inanother embodiment, the folate analog is methotrexate and thetherapeutically effective amount is usually a twice-weekly dose ofbetween about 5 mg/m² and about 25 mg/m². In another embodiment, thefolate analog is methotrexate and the therapeutically effective amountis usually a weekly intravenous dose of 50 mg/m² every two to threeweeks. In another embodiment, the folate analog is pemetrexed. Inanother embodiment, the folate analog is pemetrexed and thetherapeutically effective amount is usually at least 300 mg/m². Inanother embodiment, the folate analog is pemetrexed and thetherapeutically effective amount is usually an intravenous dose ofbetween about 300 mg/m² and about 600 mg/m² every two or three weeks. Inanother embodiment, the folate analog is pemetrexed and thetherapeutically effective amount is usually an intravenous dose of 500mg/m² every three weeks.

In another embodiment, the anti-metabolite is a purine analog and thecancer being treated is usually colorectal cancer, leukemia, or myeloma.In another embodiment, the purine analog is mercaptopurine. In anotherembodiment, the purine analog is mercaptopurine and the therapeuticallyeffective amount is usually at least 1.5 mg/kg. In another embodiment,the purine analog is mercaptopurine and the therapeutically effectiveamount is usually a daily oral dose of between about 1.5 mg/kg and about5 mg/kg. In another embodiment, the purine analog is thioguanidine. Inanother embodiment, the purine analog is thioguanidine and thetherapeutically effective amount is usually at least 2 mg/kg. In anotherembodiment, the purine analog is thioguanidine and the therapeuticallyeffective amount is usually a daily oral dose of between about 2 mg/kgand about 3 mg/kg.

In another embodiment, the anti-metabolite is an adenosine analog andthe cancer being treated is usually leukemia or lymphoma. In anotherembodiment, the adenosine analog is cladribine. In another embodiment,the adenosine analog is cladribine and the therapeutically effectiveamount is usually at least 0.09 mg/kg. In another embodiment, theadenosine analog is cladribine and the therapeutically effective amountis usually a daily intravenous dose of 0.09 mg/kg for seven days. Inanother embodiment, the adenosine analog is cladribine and thetherapeutically effective amount is usually a daily intravenous dose of4 mg/m² for seven days.

In another embodiment, the adenosine analog is pentostatin. In anotherembodiment, the adenosine analog is pentostatin and the therapeuticallyeffective amount is usually 4 mg/m². In another embodiment, theadenosine analog is pentostatin and the therapeutically effective amountis usually an intravenous dose of 4 mg/m² every other week. In anotherembodiment, the adenosine analog is pentostatin and the therapeuticallyeffective amount is usually an intravenous dose of 4 mg/m² every threeweeks.

In another embodiment, the anti-metabolite is a pyrimidine analog andthe cancer being treated is usually bladder cancer, breast cancer,colorectal cancer, esophageal cancer, head and neck cancer, leukemia,liver cancer, lymphoma, ovarian cancer, pancreatic cancer, skin cancer,or gastric cancer. In another embodiment, the pyrimidine analog iscytarabine. In another embodiment, the pyrimidine analog is cytarabineand the therapeutically effective amount is usually at least 100 mg/m².In another embodiment, the pyrimidine analog is cytarabine and thetherapeutically effective amount is usually a daily intravenous dose of100 mg/m² for seven days.

In another embodiment, the pyrimidine analog is capecitabine. In anotherembodiment, the pyrimidine analog is capecitabine and thetherapeutically effective amount is usually a daily dose of at least2000 mg/m². In another embodiment, the pyrimidine analog is capecitabineand the therapeutically effective amount is usually a twice-daily oraldose of between about 1200 mg/m² and about 1300 mg/m² for 14 days. Inanother embodiment, the pyrimidine analog is capecitabine and thetherapeutically effective amount is usually a three-week cycle wherein atwice-daily dose of about 1250 mg/m² is given for fourteen days followedby one week of rest. In another embodiment, the pyrimidine analog isfluorouracil. In another embodiment, the pyrimidine analog isfluorouracil and the therapeutically effective amount is usually atleast 10 mg/kg. In another example, the pyrimidine analog isfluorouracil and the therapeutically effective amount is usually a dailyintravenous dose of between about 300 mg/m² and about 500 mg/m² for atleast three days. In another example, the pyrimidine analog isfluorouracil and the therapeutically effective amount is usually a dailyintravenous dose of 12 mg/kg for three to five days. In anotherembodiment, the pyrimidine analog is fluorouracil and thetherapeutically effective amount is usually a weekly intravenous dose ofbetween about 10 mg/kg and about 15 mg/kg.

In another embodiment, the anti-metabolite is a substituted urea and thecancer being treated is usually head and neck cancer, leukemia,melanoma, or ovarian cancer. In another embodiment, the substituted ureais hydroxyurea. In another embodiment, the substituted urea ishydroxyurea and the therapeutically effective amount is usually at least20 mg/kg. In another embodiment, the substituted urea is hydroxyurea andthe therapeutically effective amount is usually an oral dose of 80 mg/kgevery three days. In another embodiment, the substituted urea ishydroxyurea and the therapeutically effective amount is usually a dailyoral dose of between about 20 mg/kg and about 30 mg/kg.

In another embodiment, the second agent is a platinum coordinationcomplex and the cancer being treated is usually bladder cancer, breastcancer, cervical cancer, colon cancer, head and neck cancer, leukemia,lung cancer, lymphoma, ovarian cancer, sarcoma, testicular cancer, oruterine cancer. In another embodiment, the platinum coordination complexis carboplatin. In another embodiment, the platinum coordination complexis carboplatin and the therapeutically effective amount is usually atleast 300 mg/m². In another embodiment, the platinum coordinationcomplex is carboplatin and the therapeutically effective amount isusually at least 300 mg/m² every four weeks. In another embodiment, theplatinum coordination complex is carboplatin and the therapeuticallyeffective amount is usually 300 mg/m² every four weeks. In anotherembodiment, the platinum coordination complex is carboplatin and thetherapeutically effective amount is usually at least 360 mg/m² everyfour weeks. In another embodiment, the platinum coordination complex iscisplatin. In another embodiment, the platinum coordination complex iscisplatin and the therapeutically effective amount is usually at least20 mg/m². In another embodiment, the platinum coordination complex iscisplatin and the therapeutically effective amount is usually a dailyintravenous dose of 20 mg/m² for four to five days every three to fourweeks. In another embodiment, the platinum coordination complex iscisplatin and the therapeutically effective amount is usually anintravenous dose of 50 mg/m² every three weeks.

In another embodiment, the platinum coordination complex is oxaliplatin.In another embodiment, the platinum coordination complex is oxaliplatinand the therapeutically effective amount is usually at least 75 mg/m².In another embodiment, the platinum coordination complex is oxaliplatinand the therapeutically effective amount is usually between about 50mg/m² and about 100 mg/m². In another embodiment, the platinumcoordination complex is oxaliplatin and the therapeutically effectiveamount is usually an IV infusion of between about 50 mg/m² and about 100mg/m² every two weeks. In another embodiment, the platinum coordinationcomplex is oxaliplatin and the therapeutically effective amount isusually an IV infusion of between about 80 mg/m² and about 90 mg/m²every two weeks. In another embodiment, the platinum coordinationcomplex is oxaliplatin and the therapeutically effective amount isusually a two-hour IV infusion of 85 mg/m² every two weeks.

In another embodiment, the second agent is a topoisomerase II inhibitorand the cancer being treated is usually Hodgkin's disease, leukemia,small cell lung cancer, sarcoma, or testicular cancer. In anotherembodiment, the topoisomerase II inhibitor is etoposide. In anotherembodiment, the topoisomerase II inhibitor is etoposide and thetherapeutically effective amount is usually at least 35 mg/m². Inanother embodiment, the topoisomerase II inhibitor is etoposide and thetherapeutically effective amount is usually between about 50 mg/m² andabout 100 mg/m². In another embodiment, the topoisomerase II inhibitoris etoposide and the therapeutically effective amount is usually anintravenous dose of between about 35 mg/m² and about 50 mg/m² a day atleast three times in five days every three or four weeks. In anotherembodiment, the topoisomerase II inhibitor is etoposide and thetherapeutically effective amount is usually an intravenous dose ofbetween about 50 mg/m² and about 100 mg/m² a day at least three times infive days every three or four weeks. In another embodiment, thetopoisomerase II inhibitor is etoposide and the therapeuticallyeffective amount is usually an oral dose of 100 mg/m² a day at leastthree times in five days every three or four weeks. In anotherembodiment, the topoisomerase II inhibitor is teniposide. In anotherembodiment, the topoisomerase II inhibitor is teniposide and thetherapeutically effective amount is usually at least 20 mg/m². Inanother embodiment, the topoisomerase II inhibitor is teniposide and thetherapeutically effective amount is usually a weekly dose of 100 mg/m².In another embodiment, the topoisomerase II inhibitor is teniposide andthe therapeutically effective amount is usually a twice-weekly dose of100 mg/m². In another embodiment, the topoisomerase II inhibitor isteniposide and the therapeutically effective amount is usually a dailydose of between about 20 mg/m² and about 60 mg/m² for five days. Inanother embodiment, the topoisomerase II inhibitor is teniposide and thetherapeutically effective amount is usually a daily dose of betweenabout 80 mg/m² and about 90 mg/m² for five days.

The administration mode of the compound of the present invention and aconcomitant medicament are not particularly limited, provided that thecompound of the present invention and the concomitant medicament arecombined upon administration. Such an administration mode may forexample be (1) an administration of a single formulation obtained byformulating the compound of the present invention and a concomitantmedicament simultaneously, (2) a simultaneous administration via anidentical route of two formulations obtained by formulating the compoundof the present invention and a concomitant medicament separately, (3) asequential and intermittent administration via an identical route of twoformulations obtained by formulating the compound of the presentinvention and a concomitant medicament separately, (4) a simultaneousadministration via different routes of two formulations obtained byformulating the compound of the present invention and a concomitantmedicament separately, (5) a sequential and intermittent administrationvia different routes of two formulations obtained by formulating thecompound of the present invention and a concomitant medicamentseparately (for example, the compound of the present invention followedby concomitant medicament, or inverse order) and the like.

When the compounds of the present invention are used in combination withone or more second therapeutic agents (the second active agents), thecompounds may be administered either sequentially or simultaneously byany convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus use ofpharmaceutical formulations comprising such a combination as definedabove together with a pharmaceutically acceptable carrier or excipientis a further aspect of the invention. The individual components of suchcombinations may be administered either sequentially or simultaneouslyin separate or combined pharmaceutical formulations.

When the compound of the present invention is used in combination with asecond therapeutic agent active against the same disease, the dose ofeach compound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

Similarly, it is clear for those skilled in the art that when thecompound of the present invention is used in combination with a secondtherapeutic agent active against the same disease, the dose of eachcompound may differ from that when the compound is used alone andappropriate doses can be determined by those skilled in the art.

Preferred unit dosage formulations are those containing an effectivedaily dose, as herein above recited, or an appropriate fraction thereofof the active ingredient. For example, a proposed daily dosage ofcompounds of the present invention may be preferably from about 1 mg to5000 mg, and more preferably 10 mg to 500 mg per day. As describedbefore, dosage can be changed by the individual patient, and thus notlimited to these.

The subjects to be administered the compounds of this invention orpharmaceutical compositions comprising said compounds are preferably amammalian subject including a human. The mammalian which is diagnosedwith cancer is preferable among them. The mammalian which is diagnosedwith cancer which PGE2 relates to is more preferable. Cancer which PGE2relates to includes brain tumor, bone cancer, neoplasm derived fromepithelial cells (epithelial cancer), for example, basal cell carcinoma,adenocarcinoma, gastroenterological cancer (e.g. lip cancer, oralcancer, esophageal cancer, intestinal cancer, colon cancer and gastriccancer), liver cancer, bladder cancer, pancreatic cancer, ovariancancer, cervical cancer, lung cancer, breast cancer, skin cancer (e.g.squamous cell and basal cell carcinoma), prostate cancer, renal cellcarcinoma, and other known cancers which affect the epithelial cells inthe body. The mammalian, preferably human, which is diagnosed with atleast one cancer selected from gastroenterological cancer, prostatecancer, lung cancer, and breast cancer, is more preferable.

This invention includes a method for reducing cancer cells by contactingcancer cells with the compound of the formula (I), (II), (III), or (IV)or a pharmaceutically acceptable salt thereof. The compounds of thepresent invention, their preferable embodiments and the like are thesame as described above. The method for reducing cancer cells bycontacting cancer cells with the compound of the formula (I), (II),(II), or (IV) or a pharmaceutically acceptable salt thereof is selectedaccording to the type of cancer and the like, and typically it can beconducted by oral administration or parenteral administration of theabove-described dose of the compounds represented by formula (I), (II),(M), or (IV). The second active agents may be used in the method of thepresent invention.

EXAMPLE Example 1 (EP4 Receptor Selective Antagonist: Compound A:4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoicacid)

In the stomach of K19-Wnt1/C2mE mice (Gastroenterology Volume 131, Pages1086-1095, 2006), tumor develops with an interaction of up-regulated Wntsignaling and induced COX-2/PGE2 pathway. Among human gastric cancerpatients, Wnt up-regulation is observed in 30% to 50%, and induction ofCOX-2 is observed in more than 70%. Therefore, the K19-Wnt1/C2mE ispositioned as a mouse model which extrapolates human gastric cancer interms of molecular mechanism (Nature Review Cancer, Volume 7, Pages645-658, 2007).

The experiment was conducted using five spontaneous gastric cancer modelmice at 50 weeks old (K19-Wnt1/C2mE mice). The mice develop large tumorsin stomach at 50 weeks old, and the size of tumor can be measured withX-ray CT. The sizes of tumors were measured with X-ray CT beforeadministration and at week 1, week 2, and week 3 after administration,and the sizes of tumors were compared. Compound A was continuouslyadministered at a dose of 100 mg/kg twice a day for three weeks. Amethyl cellulose was used as a vehicle. In two individuals in whichparticularly large tumor had been formed before the administration,remarkable reductions of the tumor size were observed in the first week(see FIG. 1). As shown in FIG. 1, the mean area of tumor was about 1500to about 5000 mm² in pre-administered mice, whereas after three weekstreatment, the mean area was dramatically reduced to a range of about300 to about 1100 mm², which clearly showed shrinkage of tumor bycompound A. At three weeks post-administration, effectiveness such thattumor mass almost completely disappeared in CT images was confirmed inall the five mice which were administered the compound. As clearly shownin FIG. 2, it was confirmed that the tumor was shrunk effectively byadministering compound A, compared with 55 to 60 week old K19-Wnt1/C2mEmice (n=7) which were not treated any compounds (see FIG. 2). Namely, asshown in FIG. 2, tumor was dramatically reduced by administering EP4receptor antagonists. Further, in histological analysis of excisedtissues after the treatment, disappearance of irregular glandularbranching in tumor epithelium was confirmed by visual observation.

In addition, in the graph of FIG. 2, the vertical axis representsrelative tumor volume, and “EP inhibitor” means the group administeredcompound A.

Example 2 (EP4 Receptor Selective Antagonist: Compound B:4-[(1S)-1-{[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoicacid)

Experiment was conducted using six gastric cancer model mice at 46 to 68weeks old (K19-Wnt1/C2mE mice). Compound B was continuously administeredper os at a dose of 3 mg/kg (n=2), 30 mg/kg (n=2) and vehicle control(n=2) once a day for five weeks. The measurements of tumor sizes wereconducted in the same manner as example 1. It was confirmed by X-ray CTscanning that the sizes of tumors increased in a time-dependent mannerduring test period in two vehicle controls. On the other hand, it wasconfirmed that the sizes of tumors were reduced in a dose-dependentmanner in groups administered compound B, and the effective reduction oftumor size was also observed in a group administered at a dose of 3mg/kg (see FIG. 3). In the FIG. 3, a relative value of the mean tumorarea after treatment to that before treatment (0 w) set to 100 is shownwith time. Solid square (▪) and solid diamond (♦) represent controlmodel mice. Dotted triangle (▴) and dotted cross (X) represent modelmice each administered compound B at a dose of 3 mg/kg. Solid star (*)and solid circle (●) represent model mice each administered compound Bat a dose of 30 mg/kg. Although the size of tumor increased in a groupadministered vehicle, the size of tumor dramatically reduced at any dosein groups administered compound B. In addition, remarkable shrinkages oftumor lesions were also observed in autopsy, compared with a vehiclecontrol group. Thus, it was confirmed that the size of tumordramatically reduced in groups administered compound B, compared withthat of a vehicle group.

Example 3 (Compound C:3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]urea)

The experiment was conducted in the same manner as example 2 except forusing compound C instead of compound B. As a result, compound C alsoshowed the similar effects to compound B, and it was confirmed that thetumor size dramatically reduced compared with that in a groupadministered vehicle.

Example 4

Treatment with compound A, B, or C is performed in a xenograft animalmodel of human prostate cancer (a tumor-bearing mouse prepared byimplantation of human prostate cancer cells to a nude mouse), and thechange of tumor size is examined. In this experimental system, tumorshrinkage similar to that described above is observed in the animalstreated with the compounds A, B, and C.

Example 5

Treatment with compound A, B, or C is performed in a xenograft animalmodel of human breast cancer (a tumor-bearing mouse prepared byimplantation of human breast cancer cells to a nude mouse), and thechange of tumor size is examined. In this experimental system, tumorshrinkage similar to that described above is observed in the animalstreated with the compounds A, B, and C.

Example 6

A cell line derived from mouse colon cancer, colon26, was subcutaneouslyimplanted to CD2F1 mice. (According to the method described in Int. J.Cancer, Volume 121, Pages 878-883, 2007, this model extrapolates thecolon cancer development and growth in terms of molecular mechanism.)When the mean tumor weight reached 100 mg, vehicle (n=10), compound Bonce a day at a dose of 30 mg/kg (n=10), or compound C twice a day at adose of 200 mg/kg (n=10) was administered for 20 days. The tumor weightwas calculated as (major axis)×(minor axis)²×0.5 using the measuredvalues. The FIG. 4 shows changes over time regarding the size of tumorin each group. In FIG. 4, solid square (▪), solid triangle (▴), andsolid circle (●) represent a group administered vehicle (control), agroup administered compound B, and a group administered compound C,respectively. Remarkable reductions of tumor size were observed in allgroups which were administered compounds compared with changes of tumorsize in a vehicle group.

Example 7

In the experimental system using a xenograft animal model of human coloncancer (a tumor-bearing mouse prepared by implantation of human coloncancer cells to a nude mouse), tumor shrinkage similar to that describedabove is observed in the animals treated with the compounds A, B, and C.

Example 8

A cell line derived from mouse lung cancer, LL/2, was subcutaneouslyimplanted to C57BL/6 mice. (According to the method described in CancerResearch. Volume 58, Pages 2583-2587, 1998, this model extrapolates thelung cancer development and growth.) When the mean tumor weight reached100 mg, vehicle (n=10), compound B once a day at a dose of 0.3 mg/kg(n=10), or compound C twice a day at a dose of 10 mg/kg (n=10) wasadministered for 25 days. The tumor weight was calculated as (majoraxis)×(minor axis)²×0.5 using the measured values. The FIG. 5 showschanges over time regarding the size of tumor in each group. In FIG. 5,solid square (▪), solid triangle (▴), and solid circle (●) represent agroup administered vehicle (control), a group administered compound B,and a group administered compound C, respectively. Remarkable reductionsof tumor size were observed in all groups which were administeredcompounds compared with changes of tumor size in a vehicle group.

Example 9

In the experimental system using a xenograft animal model of human lungcancer (a tumor-bearing mouse prepared by implantation of human lungcancer cells to a nude mouse), tumor shrinkage similar to that describedabove is observed in the animals treated with the compounds A, B, and C.

In conclusion, the working examples regarding antitumor effect(shrinking cancer tissues) of the compounds of the present invention aredescribed, but the present invention is not limited to these workingexamples. Thus, as previously mentioned, by use of the compounds of thepresent invention, shrinkage of cancer is observed in the cancer modelswhich PGE2 relates to. Cancer which PGE2 relates to includes braintumor, bone cancer, neoplasm derived from epithelial cells (epithelialcancer), for example, basal cell carcinoma, adenocarcinoma,gastroenterological cancer (e.g. lip cancer, oral cancer, esophagealcancer, intestinal cancer, colon cancer and gastric cancer), livercancer, bladder cancer, pancreatic cancer, ovarian cancer, cervicalcancer, lung cancer, breast cancer, skin cancer (e.g. squamous cell andbasal cell carcinoma), prostate cancer, renal cell carcinoma, and otherknown cancers which affect the epithelial cells in the body.

Therefore, the therapeutic effects can be confirmed by examining thechanges of the tumor size in a xenograft animal model of theabove-mentioned human cancer (a tumor-bearing mouse prepared byimplantation of the above-mentioned human cancer cells to a nude mouse)treated with the compounds of the present invention.

1-15. (canceled)
 16. A method for the treatment of liver cancer, whichcomprises administering an effective amount of3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]ureaor a pharmaceutically acceptable salt thereof to a human or an animal inneed thereof.
 17. The method according to claim 16, which furthercomprises administering a therapeutically effective amount of one ormore second active agents known to be useful in the treatment orprevention of liver cancer.
 18. The method according to claim 17,wherein the second active agent is at least one selected from the groupconsisting of an anti-cancer agent, an antibiotic, an immunosuppressiveagent, and a steroid.
 19. A method for the treatment of melanoma, whichcomprises administering an effective amount of3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]ureaor a pharmaceutically acceptable salt thereof to a human or an animal inneed thereof.
 20. The method according to claim 19, which furthercomprises administering a therapeutically effective amount of one ormore second active agents known to be useful in the treatment orprevention of melanoma.
 21. The method according to claim 20, whereinthe second active agent is at least one selected from the groupconsisting of an anti-cancer agent, an antibiotic, an immunosuppressiveagent, and a steroid.
 22. A method for the treatment of lymphoma, whichcomprises administering an effective amount of3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]ureaor a pharmaceutically acceptable salt thereof to a human or an animal inneed thereof.
 23. The method according to claim 22, which furthercomprises administering a therapeutically effective amount of one ormore second active agents known to be useful in the treatment orprevention of lymphoma.
 24. The method according to claim 23, whereinthe second active agent is at least one selected from the groupconsisting of an anti-cancer agent, an antibiotic, an immunosuppressiveagent, and a steroid.
 25. A method for the treatment of leukemia, whichcomprises administering an effective amount of3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]ureaor a pharmaceutically acceptable salt thereof to a human or an animal inneed thereof.
 26. The method according to claim 25, which furthercomprises administering a therapeutically effective amount of one ormore second active agents known to be useful in the treatment orprevention of leukemia.
 27. The method according to claim 26, whereinthe second active agent is at least one selected from the groupconsisting of an anti-cancer agent, an antibiotic, an immunosuppressiveagent, and a steroid.